Tretinoin is metabolite of vitamin A and used widely for curing psoriasis and acne clinically with significant effects. After all-trans tretinoin (Formula Ia) was developed, other various compounds with similar configuration are developed, such as isotretinoin (Formula Ib), acitretin (Formula Id), alitretinoin (Formula Ic) and etc., which are also used for curing psoriasis and acne. The common features of these tretinoin compounds are that, their configurations all include configuration including conjugated unsaturated carboxylic acid, substituted unsaturated hexatomic carbon ring, multiple conjugated double bonds, and they all have specific stereo configurations.

In the process of preparing tretinoin compounds, it's required to consider two important questions: the first one is how to form the group “conjugated unsaturated carboxylic acid”; the second one is how to control the stereo configuration of product. For example, the configurations of both tretinoin (Formula Ia) and acitretin (Formula Id) are all 2,4,6,8-all trans; the configurations of isotretinoin (Formula Ib) is 2-cis, 4-trans, 6-trans, 8-trans; that of alitretinoin (Formula Ic) is 2-trans, 4-trans, 6-cis, 8-trans.
In prior processes of preparation, the group “conjugated unsaturated carboxylic acid” in tretinoin compounds generally is obtained by generating the corresponding ester firstly and then hydrolyzing the ester. However, the hydrolysis process may aggravate the diversification of stereo configuration of products and generate other impurities, which makes post-treatment complicated. In order to gain end product with desired configuration, multiple recrystallization or column chromatography is generally adopted, which are not only complex but also with lower yield.
For instance, in DE1059900, the preparation process of all-trans tretinoin is as following: carrying out WITTIG reaction with [3-methyl-5-(2,6,6-trimethylcyclohexene-1-yl)-2,4-pentadiene]-triphenyl phosphonate (Formula IIa) and β-formyl crotonicacid ester (Formula IV) as raw materials; then adding alkali for hydrolysis; after hydrolysis, sequentially performing acidification, extraction and recrystallization for twice to obtain all-trans tretinoin with yield of 25-30%.

This process is complex with multiple steps; furthermore, since there are various cis isomers generated in WITTIG reaction and hydrolysis reaction, the yield is very low.
In the process for preparation acitretin in U.S. Pat. No. 4,215,215, firstly obtaining ester by [5-(4-methoxy-2,3,6-trimethyl-phenyl)-3-methyl-2,4-pentadiene]-triphenyl phosphonium bromide (Formula IId) reacting with β-formyl crotonicacid ester (Formula IV), then adding alkali for hydrolysis, carrying out acidification and extraction in sequence to gain acitretin.

The ester obtained in this process have to be hydrolyzed after separation and purification, which is also complex and with low yield.
Therefore, a process with simple synthesis method and high product yield for preparation of tretinoin compounds is desiderated.